Analysis of Molecular Networks in the Cerebellum in Chronic Schizophrenia: Modulation by Early Postnatal Life Stressors in Murine Models

Abstract

Despite the growing importance of the cerebellum as a region highly vulnerable to accumulating molecular errors in schizophrenia, limited information is available regarding altered molecular networks with potential therapeutic targets. To identify altered networks, we conducted one-shot liquid chromatography–tandem mass spectrometry in postmortem cerebellar cortex in schizophrenia and healthy individuals followed by bioinformatic analysis (PXD024937 identifier in ProteomeXchange repository). A total of 108 up-regulated proteins were enriched in stress-related proteins, half of which were also enriched in axonal cytoskeletal organization and vesicle-mediated transport. A total of 142 down-regulated proteins showed an enrichment in proteins involved in mitochondrial disease, most of which were also enriched in energy-related biological functions. Network analysis identified a mixed module of mainly axonal-related pathways for up-regulated proteins with a high number of interactions for stress-related proteins. Energy metabolism and neutrophil degranulation modules were found for down-regulated proteins. Further, two double-hit postnatal stress murine models based on maternal deprivation combined with social isolation or chronic restraint stress were used to investigate the most robust candidates of generated networks. CLASP1 from the axonal module in the model of maternal deprivation was combined with social isolation, while YWHAZ was not altered in either model. METTL7A from the degranulation pathway was reduced in both models and was identified as altered also in previous gene expression studies, while NDUFB9 from the energy network was reduced only in the model of maternal deprivation combined with social isolation. This work provides altered stress- and mitochondrial disease-related proteins involved in energy, immune and axonal networks in the cerebellum in schizophrenia as possible novel targets for therapeutic interventions and suggests that METTL7A is a possible relevant altered stress-related protein in this context.

A Novel Localization of METTL7A in Bergmann Glial Cells in Human Cerebellum

“…Indeed, METTL7A expression levels have previously been investigated in brain tissue in schizophrenia. A recent proteomic study found a reduction in METTL7A protein levels in the cerebellar cortex in schizophrenia patients and in the schizophrenia murine models [14]. In our study, we found that the main source of METTL7A in the cerebellar cortex is in the GFAP-positive cells.…”

“…Indeed, Gene Ontology classifies the biological function of METTL7A in neutrophil degranulation and its subcellular localization in lipid droplets. Studies in different areas of the human brain have revealed changes in METTL7A in schizophrenia [14][15][16]. One of these studies identified a reduction in METTL7A protein levels in the cerebellar cortex in schizophrenia subjects and stress mouse models, respectively [14].…”

“…Studies in different areas of the human brain have revealed changes in METTL7A in schizophrenia [14][15][16]. One of these studies identified a reduction in METTL7A protein levels in the cerebellar cortex in schizophrenia subjects and stress mouse models, respectively [14]. Distinct hypotheses have been postulated regarding the origin of schizophrenia [17,18]; among these models, the idea of immune dysregulation has recently been gaining importance [18][19][20][21].…”

The novel putative methyltransferase METTL7A as one prognostic biomarker potentially associated with immune infiltration in human renal cancer

“…Previous studies have found that the downregulation of METTL7A in tumor tissues predicted a poor prognosis in HCC patients [ 15 ], and that inhibiting METTL7A might help choriocarcinoma cells respond to methotrexate (MTX)-based chemotherapy [ 16 ]. In the context of neutrophil degranulation, changes in METTL7A expression may compromise the integrity of the Golgi apparatus, resulting in abnormal neutrophil secretory granule production and altering the first defense barrier of the innate immune response in chronic schizophrenia [ 31 ]. Another study investigated the role of METTL7A in preserving the integrity of the Golgi, which may be crucial for neutrophil degranulation [ 32 ].…”

Genetic polymorphism and neuroanatomical changes in schizophrenia

“…Another major area affected in schizophrenia is the cerebellum [ 167 ]. Among other functions, this region is also involved in attention, working memory, verbal learning, sensory discrimination, control of motor activity, in motor learning and has a sensorimotor calibration, depending on the context in which the individual is.…”